Defects in long-term APC repopulation ability of adult human bone marrow HSCs compared to fetal liver HSCs

Immunodeficient mice reconstituted with immune systems from patients, or Personalized Immune (PI) mice, are powerful tools for understanding human disease. Compared to mice transplanted with human fetal thymus and fetal liver-derived CD34 + cells (Hu/Hu mice; FLCs), PI mice, which are transplanted with human fetal thymus and adult bone marrow CD34 + cells (aBM), demonstrate reduced levels of human reconstitution. We characterized antigen-presenting cell (APC) and APC progenitor repopulation in human immune system (HIS) mice and detected significant reductions in blood, bone marrow and splenic APC populations in PI compared to Hu/Hu mice. APC progenitors and hematopoietic stem cells (HSCs) were less abundant in aBM compared to FLC cell preparations and this reduction in APC progenitors was reflected in the BM of PI compared to Hu/Hu mice 14-20 weeks post-transplant. The number of HSCs increased in PI mice compared to the originally infused BM cells and maintained functional repopulation potential, as bone marrow from some PI mice 28 weeks post-transplant generated human myeloid and lymphoid cells in secondary recipients. Moreover, long-term PI mouse BM contained functional T cell progenitors, evidenced by thymopoiesis in thymic organ cultures. Injection of aBM cells directly into the bone marrow cavity, transgenic expression of hematopoietic cytokines and co-infusion of human bone marrow-derived mesenchymal stem cells synergized to enhance long-term B cell and monocyte levels in PI mice. These improvements allow a sustained timeframe of 18-22 weeks where APCs and T cells are present and greater flexibility for modeling immune disease pathogenesis and immunotherapies in PI mice.